Bladder cancer kills approximately 13,000 Americans per year. At least half of these deaths are preventable with no improvements in screening because they occur in people who were initially diagnosed with superficial bladder cancer. The problem is that bladder cancer recurs in over 50% of patients over 5 years, and even though only about 25% of these recurrences progress to muscle invasive disease, the numbers account for about half the deaths. Our hypothesis is that the high recurrence rate is due to cancer cells that may not be recognizable because they have been phenotypically suppressed by the normal extracellular matrix and emerge later as recurrent, often progressive disease. These cells are resistant to chemotherapy or other therapy because they do not express the malignant phenotype. Research in our laboratory has identified a novel screening system designed specifically to identify drugs that target cancer cells that are suppressed by normal extracellular matrix. The aims of this proposal are to further develop this novel approach to develop drugs applicable to prevention of recurrence of bladder cancer and treatment of micrometastatic bladder cancer by eliminating suppressed cancer cells. When used in conjunction with surgery and BCG to eliminate cells expressing the malignant phenotype, it is our hypothesis that the toll from bladder cancer can be markedly diminished along with much of the high costs to the health care system engendered from the high recurrence rate. The specific aims are: (1) Screen a 20,000 compound library to increase the number of candidate compounds active against suppressed bladder cancer cells;(2) Test the 3 most active compounds against in vivo models of bladder cancer. The first aim will be achieved by screening for differential cytotoxic activity against bladder cancer cells growing on a normal extracellular matrix vs. on plastic and further winnowing out compounds that are not active against multiple cell lines. The second aim will be achieved using flank and orthotopic xenograft models involving implantation of human bladder cancer cells to demonstrate activity against both locally suppressed cells and micrometastatic cells. These studies will form the basis for an Investigational New Drug application to support Phase I/II testing in humans. This application forms a key piece to the business plan of DormaTarg, Inc. By identifying additional lead compounds we not only increase our pipeline, but also provide additional instances of drugs that will allow us to generalize as to the kinds of compounds that will target dormant cancer cells. PUBLIC HEALTH RELEVANCE: A novel screening approach to identifying drugs active against suppressed cancer cells has been licensed by DormaTarg, Inc. We believe these cells, which appear normal to a pathologist but which contain the mutations of cancer cells, can be killed by novel drugs and therefore are the key to reducing the toll from bladder cancer.